Biology subjects

Ho, P.-Y.

Publications and source records attributed to Ho, P.-Y..

12 recordsLinked to original sources

bioRxiv2026

Coarse-graining metabolic networks via feature learning reveals cross-species growth laws

Bacterial growth and the underlying metabolic networks are highly dissimilar across species, posing a fundamental challenge for bioengineering tasks involving diverse species. For a given species across nutrient environments, growth is regulated via proteome allocation, which gives rise to linear relationships between growth and the sizes of coarse-grained proteome sectors. However, whether and how coarse-grained growth predictors generalize across species remain unclear. Here, using genome-scale metabolic models, we discover a simple cross-species trend in which the monoculture growth of a species is proportional to the number of nutrients it utilizes, indicating that the latter is a regulatory feature that is conserved across species. By coarse-graining metabolic networks using feature learning, we identify novel proteome sectors whose sizes exhibit cross-species correlations with growth in wide-ranging experiments, suggesting that these sectors are also conserved regulatory features. We further show that the sectors enable a predictive encoding of proteome costs and growth benefits, thereby providing a potential explanation for how coarse-grained network features emerge to be simple determinants of growth across diverse metabolic networks.

systems biology↗

bioRxiv2026

Phage-based microbiome manipulation reveals ecological interactions within gut communities

Mechanistic understanding of gut ecology is limited by the availability of tools for precise manipulation of microbiome composition. Here, we isolate lytic phages to enable targeted removal of gut commensal Escherichia fergusonii (Ef) from complex, undefined stool-derived in vitro communities. A single phage drove resistance without fitness cost in monoculture, but resistant Ef exhibited reduced fitness in communities, enabling expansion of closely related Proteobacteria. Resistance arose via reversible promoter inversion linked to outer-membrane function. A phage cocktail overcame resistance to achieve Ef knockout across communities with minimal collateral effects. Using knockout communities, we show that Ef is necessary and sufficient for preventing Salmonella invasion. Replacement with an Ef transposon-mutant library revealed that community-specific fitness defects are enriched in genes involved in outer-membrane assembly. Disruption of these genes sensitized Ef to antagonistic community members, highlighting interspecies warfare as a key driver of microbiome ecology. These results establish phage-mediated perturbation as a framework for linking species to community-level function and for enabling precision microbiome engineering.

microbiology↗

bioRxiv2024

The network structure of cross-feeding impacts microbial community diversity under growth-inhibiting stresses

Perturbations such as dietary shifts and drug treatment can reduce gut microbiome diversity, with negative health effects on the host, but predicting changes to community diversity is challenging due to the many mechanisms by which species interact. While both nutrient competition and cross-feeding can play major roles in microbiota assembly, the effect of environmental stresses such as antibiotics is typically studied experimentally in monoculture, and most theoretical studies have focused on communities that interact via nutrient competition alone. To investigate the interplay between nutrient competition, stresses that inhibit growth, and cross-feeding, we introduce a consumer-resource model that includes all three factors and captures a wide range of cross-feeding network architectures with a single parameter. For three-species communities, we found that coexistence during narrow-spectrum growth inhibition was maximal with a cyclic cross-feeding network, while fully connected cross-feeding networks maximized coexistence during broad-spectrum growth inhibition. However, the effects of cyclic cross-feeding were particularly sensitive to community size and the number of targeted species; for communities with more than six species and resources, cyclic cross-feeding can be detrimental to coexistence due to instability. Our findings highlight the complex effects of cross-feeding network architecture on coexistence when growth inhibition reshapes the nutrient competition landscape, with potential applications to microbial communities in all natural environments, where they are often exposed to agents such as drugs, temperature, and pH modulation.

ecology↗

bioRxiv2024

Nutrient competition predicts gut microbiome restructuring under drug perturbations

Human gut commensal bacteria are routinely exposed to various stresses, including therapeutic drugs, and collateral effects are difficult to predict. To systematically interrogate community-level effects of drug perturbations, we screened stool-derived in vitro communities with 707 clinically relevant small molecules. Across [~]5,000 community-drug interaction conditions, compositional and metabolomic responses were predictably impacted by nutrient competition, with certain species exhibiting improved growth due to adverse impacts on competitors. Changes to community composition were generally reversed by reseeding with the original community, although occasionally species promotion was long-lasting, due to higher-order interactions, even when the competitor was reseeded. Despite strong selection pressures, emergence of resistance within communities was infrequent. Finally, while qualitative species responses to drug perturbations were conserved across community contexts, nutrient competition quantitatively affected their abundances, consistent with predictions of consumer-resource models. Our study reveals that quantitative understanding of the interaction landscape, particularly nutrient competition, can be used to anticipate and potentially mitigate side effects of drug treatment on the gut microbiota.

microbiology↗

bioRxiv2024

Challenges in quantifying functional redundancy and selection in microbial communities

Microbiomes can exhibit large variations in species abundances but high reproducibility in abundances of functional units, an observation often considered evidence for functional redundancy. Based on such reduction in functional variability, selection is hypothesized to act on functional units in these ecosystems. However, the link between functional redundancy and selection remains unclear. Here, we show that reduction in functional variability does not always imply selection on functional profiles. We propose empirical null models to account for the confounding effects of statistical averaging and bias toward environment-independent beneficial functions. We apply our models to existing data sets, and find that the abundances of metabolic groups within microbial communities from bromeliad foliage do not exhibit any evidence of the previously hypothesized functional selection. By contrast, communities of soil bacteria or human gut commensals grown in vitro are selected for metabolic capabilities. By separating the effects of averaging and functional bias on functional variability, we find that the appearance of functional selection in gut microbiome samples from the Human Microbiome Project is artifactual, and that there is no evidence of selection for any molecular function represented by KEGG orthology. These concepts articulate a basic framework for quantifying functional redundancy and selection, advancing our understanding of the mapping between microbiome taxonomy and function.

ecology↗

bioRxiv2023

Assembly of gut-derived bacterial communities follows "early-bird" resource utilization dynamics

Diet can impact host health through changes to the gut microbiota, yet we lack mechanistic understanding linking nutrient availability and microbiota composition. Here, we use thousands of microbial communities cultured in vitro from human feces to uncover simple assembly rules and develop a predictive model of community composition upon addition of single nutrients from central carbon metabolism to a complex medium. Community membership was largely determined by the donor feces, whereas relative abundances were determined by the supplemental carbon source. The absolute abundance of most taxa was independent of the supplementing nutrient, due to the ability of fast-growing organisms to quickly exhaust their niche in the complex medium and then exploit and monopolize the supplemental carbon source. Relative abundances of dominant taxa could be predicted from the nutritional preferences and growth dynamics of species in isolation, and exceptions were consistent with strain-level variation in growth capabilities. Our study reveals that community assembly follows simple rules of nutrient utilization dynamics and provides a predictive framework for manipulating gut commensal communities through nutritional perturbations.

microbiology↗

bioRxiv2022

Oral Delivery of Kidney Targeting Nanotherapeutics for Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder. Although a variety of candidate drugs have been found to modulate cystogenesis in animal studies, results from clinical trials have often been unfavorable due to low renal bioavailability and drug-induced side effects. To mitigate this, nanoparticles can be designed to deliver drugs directly to the target organ to increase effective dose while limiting off-target side effects. Unfortunately, there are no kidney-targeted nanomedicines clinically available, and most of the existing FDA-approved nanoparticles require intravenous administration which is not suitable for ADPKD that require lifelong therapy. To address this, we developed an oral drug delivery system using chitosan nanoparticles (CS-NP) that were loaded with peptide amphiphile micelles carrying metformin (met), an ADPKD drug candidate (CS-KM-met). We previously showed that CS-NP can shield met in the gastrointestinal tract; thus, we hypothesized that CS-NP could also enhance bioavailability of kidney-targeting micelles (KMs) upon oral administration. Specifically, we measured the loading capacity of KM-met in CS-NP, evaluated the stability of CS-KM-met under acidic conditions that mimic the gastric environment, and measured in vitro therapeutic effects. Upon oral administration in C57BL/6J mice, CS-KM-met showed significantly greater bioavailability and accumulation in the kidneys as compared to KM-met without CS-NP or free met for up to 24 hours. As such, CS-KM-met showed enhanced therapeutic efficacy in vivo upon oral administration in PKD mice (Pkd1fl/fl; Pax8-rtTA; Tet-O-Cre) compared to KM-met only. Herein, we demonstrate the potential of an oral delivery nanoformulation for the treatment of chronic kidney diseases such as ADPKD for the first time.

bioengineering↗

bioRxiv2022

Antibiotic effects on microbial communities are modulated by resource competition

Antibiotic treatment significantly impacts the human gut microbiota, but quantitative understanding of how antibiotics affect community diversity is lacking. Here, we build on classical ecological models of resource competition to investigate community responses to antibiotic-induced species-specific death rates. Our analyses highlight the complex dependence of species coexistence that can arise from the interplay of resource competition and antibiotic activity, independent of other biological mechanisms. We show that resource competition can cause richness to change non-monotonically as antibiotic concentrations are increased. We identified resource competition structures that cause richness to depend on the order of sequential application of antibiotics (non-transitivity), and the emergence of synergistic and antagonistic effects under simultaneous application of multiple antibiotics (non-additivity). These complex behaviors can be prevalent, especially when generalist consumers are targeted. Communities can be prone to either synergism or antagonism, but typically not both, and antagonism is more common. Furthermore, we identify a striking overlap in competition structures that lead to non-transitivity during antibiotic sequences and those that lead to non-additivity during antibiotic combination, suggesting that our analysis is broadly applicable across a wide range of clinically relevant antibiotic treatment schemes. In sum, our results will facilitate the engineering of community dynamics via deleterious agents.

ecology↗

bioRxiv2022

Resource competition predicts assembly of in vitro gut bacterial communities

Members of microbial communities interact via a plethora of mechanisms, including resource competition, cross-feeding, and pH modulation. However, the relative contributions of these mechanisms to community dynamics remain uncharacterized. Here, we develop a framework to distinguish the effects of resource competition from other interaction mechanisms by integrating data from growth measurements in spent media, synthetic community assembly, and metabolomics with consumer-resource models. When applied to human gut commensals, our framework revealed that resource competition alone could explain most pairwise interactions. The resource-competition landscape inferred from metabolomic profiles of individual species predicted assembly compositions, demonstrating that resource competition is a dominant driver of in vitro community assembly. Moreover, the identification and incorporation of interactions other than resource competition, including pH-mediated effects and cross-feeding, improved model predictions. Our work provides an experimental and modeling framework to characterize and quantify interspecies interactions in vitro that should advance mechanistically principled engineering of microbial communities.

ecology↗

bioRxiv2021

In vivo augmentation of a complex gut bacterial community

Efforts to model the human gut microbiome in mice have led to important insights into the mechanisms of host-microbe interactions. However, the model communities studied to date have been defined or complex but not both, limiting their utility. In accompanying work, we constructed a complex synthetic community (104 strains, hCom1) containing the most common taxa in the human gut microbiome. Here, we used an iterative experimental process to improve hCom1 by filling open metabolic and/or anatomical niches. When we colonized germ-free mice with hCom1 and then challenged it with a human fecal sample, the consortium exhibited surprising stability; 89% of the cells and 58% of the taxa derive from the original community, and the pre- and post-challenge communities share a similar overall structure. We used these data to construct a second version of the community, adding 22 strains that engrafted following fecal challenge and omitting 7 that dropped out (119 strains, hCom2). In gnotobiotic mice, hCom2 exhibited increased stability to fecal challenge and robust colonization resistance against pathogenic Escherichia coli. Mice colonized by hCom2 versus human feces are similar in terms of microbiota-derived metabolites, immune cell profile, and bacterial density in the gut, suggesting that this consortium is a prototype of a model system for the human gut microbiome.

microbiology↗

bioRxiv2021

Competition for fluctuating resources reproduces statistics of species abundance over time across wide-ranging microbiotas

Across diverse microbiotas, species abundances vary in time with distinctive statistical behaviors that appear to generalize across hosts, but the origins and implications of these patterns remain unclear. Here, we show that many of these patterns can be quantitatively recapitulated by a simple class of resource-competition models, in which the metabolic capabilities of different species are randomly drawn from a common statistical ensemble. Our coarse-grained model parametrizes the intrinsic consumer-resource properties of a community using a small number of macroscopic parameters, including the total number of resources, typical resource fluctuations over time, and the average overlap in resource-consumption profiles across species. We elucidate how variation in these parameters affects various time series statistics, enabling macroscopic parameter estimation and comparison across wide-ranging microbiotas, including the human gut, saliva, and vagina, as well as mouse gut and rice. The successful recapitulation of time series statistics across microbiotas suggests that resource competition generally acts as a dominant driver of community dynamics. Our work unifies numerous time series patterns under one model, clarifies their origins, and provides a framework to infer macroscopic parameters of resource competition from longitudinal studies of microbial communities.

ecology↗

bioRxiv2019

A model for the regulation of the timing of cell division by the circadian clock in the cyanobacterium Synechococcus elongatus

1Cells of the cyanobacterium Synechococcus elongatus possess a circadian clock in the form of three core clock proteins (the Kai proteins) whose concentrations and phosphorylation states oscillate with daily periodicity under constant conditions [1]. The circadian clock regulates the cell cycle such that the timing of cell divisions is biased towards certain times during the circadian period [2, 3, 4, 5], but the mechanism underlying how the clock regulates division timing remains unclear. Here, we propose a mechanism in which a protein limiting for division accumulates at a rate proportional to cell volume growth and modulated by the clock. This \"modulated rates\" model, in which the clock signal is integrated over time to affect division timing, differs fundamentally from the previously proposed \"gating\" concept, in which the clock is assumed to suppress divisions during a specific time window [2, 3]. We found that while both models can capture the single-cell statistics of division timing in S. elongatus, only the modulated rates model robustly places divisions away from darkness during changes in the environment. Moreover, within the framework of the modulated rates model, existing experiments on S. elongatus are consistent with the simple mechanism that division timing is regulated by the accumulation of a division limiting protein in phase with genes whose activity peak at dusk.

microbiology↗